Vasoactive intestinal polypeptide in algodystrophy.
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Humans↗
Biomedical subjects
M A Ghatei
Publications and source records attributed to M A Ghatei.
Effect of synthetic human glucose-dependent insulinotropic polypeptide (hGIP) on the release of insulin in man.
During an oral glucose tolerance test (oGTT) and an isoglycaemic intravenous glucose infusion, blood glucose and the responses of insulin and glucose-dependent insulinotropic polypeptide (GIP) were measured in six healthy volunteers. On a subsequent occasion a constant infusion of human synthetic GIP (2 pmol kg-1 min-1 for 30 min and 0.5 pmol kg-1 min-1 for another 30 min was given to each subject, again with a simultaneous infusion of glucose to maintain isoglycaemia to the oGTT. During the oGTT, plasma GIP concentrations rose from 92 +/- 18 pmol 1(-1) to 257 +/- 42 pmol 1(-1) 60 min after ingestion of glucose (mean +/- SEM). When glucose was administered intravenously plasma GIP levels did not rise significantly over basal. The infusion of hGIP mimicked the physiological plasma GIP response after oral glucose during the first 60 min of the study. Plasma insulin concentrations were significantly lower between 45 and 60 min than during the oGTT (438 +/- 67 vs. 200 +/- 48 pmol 1(-1); P less than 0.02; 465 +/- 96 vs. 207 +/- 48 pmol 1(-1); P less than 0.01). However, the total and incremental integrated insulin responses during the first 60 min of the study were, though lower, not significantly different from the oGTT experiment when glucose and hGIP were infused simultaneously. Thus, in the presence of mild physiological hyperglycaemia, human GIP is able to enhance the initial insulin response almost equivalently to the stimulus provided by oral glucose. Decreased insulin concentrations during porcine GIP infusions in previous experiments might be due to sequence differences between human and porcine GIP.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Neuropeptide Y and the anterior pituitary.
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Animals↗
Is peptide YY trophic to the intestinal epithelium of parenterally fed rats?
Four groups of intravenously maintained rats were infused with 0, 5, 20 or 80 micrograms/rat/day of peptide tyrosine tyrosine (PYY) for 3 days. After 3 days the rats were injected with 1 mg/kg of vincristine in order to arrest cells entering metaphase and were killed 2 h later. The gastrointestinal tract was removed, weighed and fixed. Samples of small intestine and colon were stained, microdissected and the mean number of metaphases per crypt determined. No significant effect on intestinal tissue mass or the 2-hour collection of metaphases was observed. It is concluded that PYY is not trophic to the gastrointestinal tract.
Animals↗
Effect of ACTH on VIP and galanin release from the pituitary.
The effect of adrenocorticotropin (ACTH) on the release of four regulatory peptides from the anterior pituitary of male rats has been studied using an in vitro perfusion system. Quartered anterior pituitaries from male adult Wistar rats were perfused with buffer containing different concentrations of ACTH and, subsequently, 56 mM KCl. Fractions of 1.5 ml were collected at 3 min intervals and analyzed for vasoactive intestinal peptide (VIP), galanin, 7B2, and substance P, using specific radioimmunoassays. Concentrations of 0.02, 0.1, 0.2, and 0.4 microM ACTH produced increases of 117 +/- 50%, 155 +/- 90%, 163 +/- 14%, and 161 +/- 3% (mean + SE), respectively, of basal release of VIP (P less than 0.001). However, concentrations of 1 microM and 2 microM ACTH suppressed VIP release to 74 +/- 6% and 47 +/- 4%, respectively, compared to basal release (P less than 0.001). Results for galanin release were similar: concentrations of 0.02, 0.1, 0.2, and 0.4 microM ACTH increased galanin release to 129 +/- 4%, 136 +/- 8%, 143 +/- 9%, and 133 +/- 9% of basal release (P less than 0.001) and 1 and 2 microM ACTH provoked a suppression of 52 +/- 7% and 50 +/- 13%, respectively, compared with basal release (P less than 0.001). Doses of ACTH that altered the secretion of VIP and galanin had no effect on 7B2 and substance P release. These results demonstrate that ACTH causes a release of pituitary VIP and galanin in vitro and, moreover, that this is a biphasic phenomenon.
Adrenocorticotropic Hormone↗
The influence of thyroid hormone status on the hypothalamo-hypophyseal growth hormone axis.
Growth hormone (GH) synthesis is known to be impaired by either abnormally high or low levels of thyroid hormone. To determine the effects of these conditions on the central regulation of GH secretion, we have examined their effects on the hypothalamic regulatory peptides GH-releasing hormone (GH-RH) and somatostatin (SRIF). In thyroidectomized rat hypothalamus, a dramatic increase in GH-RH mRNA occurred in parallel with a decrease in peptide content. The significance of this phenomenon is uncertain and might possibly reflect some posttranscriptional derangement of GH-RH synthesis or an increased rate of GH-RH synthesis and release. In the hyperthyroid group, GH-RH showed significant decreases in both peptide and mRNA levels that might possibly reflect a decrease in GH-RH synthesis and secretion. No change was observed in SRIF peptide or mRNA levels in either thyroidectomized or T4-treated animals. As expected, GH mRNA levels in the anterior pituitary were dramatically decreased by thyroidectomy and unaffected by T4 treatment. In addition, in thyroidectomized pituitaries, the mature GH mRNA was observed to alter its structure, increasing in size by approximately 100 nucleotides. This increase in size was found to result from an increase in poly(A) tail length, the significance of which is as yet unclear.
Animals↗
Release of substance P from rat hypothalamus and pituitary by endothelin.
Endothelin-1 is a 21 amino acid peptide originally isolated from porcine aortic endothelium and has recently been localized within the central nervous system. We have administered endothelin-1 in a dynamic perfusion system in order to study its possible effects on the rat hypothalamus and anterior pituitary. Tissue (hypothalami or quartered pituitaries) was placed into plastic chambers and was perfused with oxygenated Krebs-bicarbonate solution. After an interval to establish stable basal peptide release, endothelin-1 was administered at two doses (0.1 and 1 microM) and the release of substance P, vasoactive intestinal peptide, 7B2, and somatostatin was measured, the last being detectable only in hypothalamic perfusates. Both concentrations of endothelin-1 led to a significant increase (P less than 0.01) in the release of substance P from the hypothalamus and pituitary, but not of vasoactive intestinal peptide, 7B2, or somatostatin. Thus after the 0.1 microM and 1 microM endothelin-1 perfusion substance P release from the hypothalamus increased by 125 +/- 5% and 215 +/- 15% (mean +/- SEM) of basal and from the pituitary by 168 +/- 8% and 276 +/- 15% (mean +/- SEM). No change occurred in the output of ACTH or other pituitary hormones. The release of substance P from hypothalamus or pituitary after stimulation with endothelin-1 was not blocked when a calcium free medium was used. Endothelin-1 binding sites were identified on rat pituitary cell membranes. These findings suggest the possibility that endothelin may act as a paracrine substance, neurotransmitter, or neuromodulator in the hypothalamo-pituitary axis.
Animals↗
Effect of endocrine manipulation on anterior pituitary galanin in the rat.
Galanin is widely distributed throughout the rat neural and endocrine system. The highest concentrations are found in the anterior pituitary, and it can influence classical pituitary hormone secretion. The effects of endocrine manipulation on pituitary galanin content, mRNA, and immunostaining have been investigated in the rat. In females, medical (39 +/- 4 fmol/gland), surgical (33 +/- 2), or combined (28 +/- 6) castration resulted in a highly significant decrease in galanin content (control, 223 +/- 14; P less than 0.0001). Estrogen in physiological and pharmacological doses produced a significant increase in galanin content (368 +/- 14 and 373 +/- 13, respectively; P less than 0.01) associated with an increase in galanin mRNA content. In the male, high dose dexamethasone and thyroidectomy caused a fall in galanin content, while galanin mRNA levels showed a rise and fall, respectively. Adrenalectomy caused a rise in galanin content, while adrenalectomy and castration produced a dramatic decrease in tissue galanin content. No change in galanin mRNA was observed in these groups. Galanin immunostaining paralleled the results of tissue content in all groups examined, except in the medically castrated group, in which there was some intragroup variation in staining patterns. In normal and high-dose estrogen-treated females, galanin expression was seen mainly in lactotrophs, with a small number of somatotrophs and thyrotrophs staining. In the male, galanin expression was confined to somatotrophs and thyrotrophs. Galanin mRNA was localized at the cellular level by in situ hybridization. In the normal pituitary only scattered lactotrophs contained message, while in high-dose estrogen-treated animals the number of positive cells, mostly lactotrophs, was vastly increased. Thus, the cellular localization of galanin immunostaining varies between the sexes. Galanin peptide and mRNA levels in the pituitary are powerfully influenced by endocrine status.
Adrenalectomy↗
The regulation of neuropeptide expression in rat anterior pituitary following chronic manipulation of estrogen status: a comparison between substance P, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.
The neuropeptides substance P, neuropeptide Y, neurotensin, and vasoactive intestinal peptide are present in normal rat anterior pituitary gland and hypothalamus and can influence the secretion of classical pituitary hormones. We investigated the effects of estrogen manipulation on pituitary and hypothalamic expression of these four peptides by specific RIAs and cDNA probe analysis. Surgical ovariectomy produced a significant rise in the pituitary content of substance P immunoreactivity (IR) (130.2 +/- 4.8 fmol/gland vs. control 29.1 +/- 2.2, P less than 0.001), neuropeptide Y IR (34.9 +/- 3.9 vs. 19.6 +/- 2.0, P less than 0.05) and neurotensin IR (85.1 +/- 8.2 vs. 62.4 +/- 7.2, P less than 0.05), while vasoactive intestinal peptide IR showed a fall (201.2 +/- 18.8 vs. 285.4 +/- 25.9, P less than 0.05). These patterns were reversed with estrogen replacement or high dose estrogen treatment. Changes in peptide content were accompanied by parallel changes in the mRNA for each peptide. Treatment with an antiestrogen (tamoxifen) resulted in no change in substance P, neuropeptide Y, and neurotensin expression, while vasoactive intestinal peptide IR content decreased to below the assay detection limit. Hypothalamic expression of these peptides did not change with any of the treatments. These results indicate that: 1) the control of the pituitary expression of the four peptides under the influence of estrogen occurs predominantly at the level of gene transcription and 2) normalization of the castration induced changes by exogenous estrogen replacement suggests the changes to be mediated by the absence of this steroid. The regulation of the pituitary expression of these peptides by estrogen support the possibility of their having an autocrine or paracrine role.
Animals↗
Localization of immunoreactivity for calcitonin gene-related peptide in the rat anterior pituitary during ontogeny and gonadal steroid manipulations and detection of its messenger ribonucleic acid.
Localization of calcitonin gene-related peptide (CGRP) expression in the rat anterior pituitary and its changes during ontogeny and after gonadal steroid manipulations were studied by immunocytochemistry, RIA, and in situ hybridization. Colocalization studies and the combined use of immunocytochemistry and in situ hybridization revealed that CGRP immunoreactivity is localized mainly in gonadotropes and alpha- and beta-CGRP messenger RNAs were detected in CGRP-immunoreactive cells. Immunoreactivity for CGRP also was detected in nerve fibers and colocalized with substance P immunoreactivity. Cells immunoreactive to CGRP antiserum were first detected in fetal rats at gestational day 18, and the incidence considerably increased between postnatal days 5 and 14. CGRP immunoreactivity was low in control adults of both sexes and in pregnant and ovariectomized females but increased in lactating, estrogen-supplemented ovariectomized and high-dose estrogen-treated females, and in high-dose estrogen-treated and castrated males. Testosterone supplement suppressed the effect of castration on CGRP immunoreactivity in males. Quantities of extractable immunoreactive CGRP under conditions of estrogen manipulation corresponded well to the immunocytochemical findings (females: controls, 96.4 +/- 13.1 fmol/gland; ovariectomized, 107.6 +/- 19.2; high-dose estrogen-treated, 212 +/- 23.0; estrogen-supplemented ovariectomized, 680 +/- 42.1). The present study suggests that pituitary CGRP is synthesized and stored in gonadotropes, is modulated by gonadal steroids, and may have a functional link with gonadotropins.
Aging↗
Endothelin-like immunoreactivity in human breast cyst fluid.
Immunoreactive endothelin has been detected in 21 of 43 samples of breast cyst fluid (21 cases; 3.5 +/- 0.6 pmol/l, mean +/- SEM. Other 22 cases; not detectable, less than 0.5 pmol/l). Fast protein liquid chromatographic analysis of the immunoreactive endothelin of pooled breast cyst fluid showed two immunoreactive peaks; one in the void volume and the other in the position of endothelin-1. It is probable that endothelin-1 is produced by the epithelial cells lining breast cysts, but significance of the presence of endothelin-1 in breast cyst fluid remains to be elucidated.
Chromatography, High Pressure Liquid↗
Amylin and amylin-amide lack an acute effect on blood glucose and insulin.
Amylin-amide has been implicated in the pathogenesis of type II diabetes due to its proposed inhibitory effect on insulin release from beta cells of the pancreatic islets, and on glucose uptake by the skeletal muscle. In experiments with rats and rabbits we failed to demonstrate these anti-insulin actions of amylin and amylin-amide. A single bolus dose of the two peptides (500 pmol) administered i.v. failed to suppress plasma insulin levels or to elevate blood glucose levels. The continuous infusion of amylin-amide into rabbits also failed to suppress the release of insulin in response to hyperglycaemia produced by an i.v. bolus injection of glucose. These in vivo observations imply that the amylin peptides may not have a primary physiological role in carbohydrate metabolism, but in view of our previous findings, we speculate that the peptide has a more prominent role in calcium homeostasis.
Amyloid↗
Glucagon-like peptide-1 (7-36)-NH2: a physiological inhibitor of gastric acid secretion in man.
Glucagon-like peptide (GLP)-1 (7-36)-NH2 is a peptide found in the mucosal endocrine cells of the intestine, and plasma levels of GLP-1 (7-36)-NH2 immunoreactivity show a rise after the ingestion of a fat or mixed-component meal. We investigated the effects of physiological infusion of GLP-1 (7-36)-NH2 on a submaximal gastric acid secretion in healthy volunteers at a rate known to mimic the observed postprandial rise in plasma concentrations. Corrected gastric acid output decreased to less than 50% and volume output to 33% of stimulated values. After the infusion, the secretion of gastric acid recovered immediately to preinhibition values. These results suggest a novel role for GLP-1 (7-36)-NH2 as a physiological inhibitor of gastric acid secretion in man.
Adult↗
Islet amyloid polypeptide-like immunoreactivity (amylin) in rats treated with dexamethasone and streptozotocin.
Islet amyloid polypeptide (IAPP) is a 37 amino acid peptide present in pancreatic beta-cells. Pancreatic and circulating IAPP concentrations in rat models of diabetes were measured using a specific radioimmunoassay. Pancreatic IAPP-like immunoreactivity (IAPP-IR) in dexamethasone-treated rats was twice that of the control rats (1571 +/- 137 vs 657 +/- 176 (S.E.M.; n = 6) pmol/g), and this was reflected by similar changes in the plasma IAPP-IR (272 +/- 17 vs 102 +/- 10 pmol/l). In streptozotocin-treated rats, pancreatic IAPP-IR (200 +/- 90 pmol/g) was reduced compared with controls. There was a significant positive correlation between pancreatic and plasma IAPP-IR and insulin, with r values of 0.82 and 0.91 for the plasma and pancreas respectively. Characterization of pancreatic immunoreactivity, using gel chromatography, revealed two peaks of IAPP-IR, one which coeluted with synthetic human amidated IAPP and another peak, presumably a fragment or breakdown product, which eluted later. Chromatography of the plasma IAPP-IR revealed that greater than 90% of the IAPP-IR eluted in the void volume, although the remaining IR coeluted with the synthetic IAPP standard. These results are not straightforwardly compatible with the suggested role for IAPP as a hormonal, paracrine or autocrine inhibitory regulator of insulin secretion in the maintenance of carbohydrate homeostasis.
Amyloid↗
The influence of adrenal hormone status on neuroendocrine peptides in the rat anterior pituitary gland.
Neuropeptide Y (NPY), neurotensin (NT), substance P (SP) and vasoactive intestinal peptide (VIP) are four structurally unrelated neuroendocrine peptides which affect anterior pituitary function. All four peptides appear to be locally synthesized in the anterior pituitary gland and have been shown to be regulated by thyroid and/or sex hormone status. We show here that NT, SP and VIP but not NPY are influenced by adrenal hormone status in the male rat pituitary gland. Adrenalectomy increased the content of VIP (35.4 +/- 4.0 (S.E.M.) vs control 11.9 +/- 1.1 pmol/g wet weight) but decreased that of SP (18.8 +/- 2.3 vs control 36.7 +/- 3.5 pmol/g wet weight). Adrenalectomy combined with castration decreased the content of SP (14.6 +/- 3.5 vs control 36.7 +/- 3.9 pmol/g wet weight) but had no effect on VIP content. Treatment with dexamethasone produced significant decreases in NT, SP and VIP contents (17.8 +/- 2.3 vs control 32.6 +/- 3.4 pmol/g wet weight, 5.5 +/- 0.9 vs control 36.7 +/- 3.9 pmol/g wet weight and 4.2 +/- 0.6 vs control 11.9 +/- 1.1 pmol/g wet weight respectively). The changes in pituitary peptide contents occurred in parallel with changes in mRNA levels, suggesting that alterations in glucocorticoid hormone status can alter the synthesis of these peptides. These results, together with the known effects of these neuroendocrine peptides suggest possible functions for locally produced SP and VIP in regulating the secretion of adrenocorticotrophin and/or other pro-opiomelanocortin-derived peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal Cortex Hormones↗
Hypothalamic regulatory peptide disturbances in the spontaneously obese JCR: LA-corpulent rat.
Central and lateral hypothalamic concentrations of 9 regulatory peptides implicated in the control of feeding behaviour were measured in corpulent (cp/cp) JCR:LA-cp rats which develop spontaneous obesity, hyperinsulinaemia and hyperlipidaemia, and in lean (+/?) controls. In female cp/cp rats, central hypothalamic levels of neuropeptide Y (NPY), neurotensin, somatostatin and substance P were significantly lower (p less than 0.02) than in lean female controls. Following food restriction with a 16% reduction in body weight, these differences were apparently reversed and there were also significant rises in the lateral hypothalamic concentrations of neurotensin and of galanin. The other 4 peptides examined (bombesin, calcitonin gene-related peptide, neuromedin B and vasoactive intestinal peptide) did not differ significantly between cp/cp and lean females, either fed freely or food-restricted. Male cp/cp rats showed no significant differences from lean males in central or lateral hypothalamic concentrations of any of the 9 peptides. NPY and galanin are powerful and specific central appetite stimulants, whereas neurotensin, substance P and somatostatin inhibit feeding when injected centrally. Disturbances in these putative appetite-regulating peptides may be involved in the hyperphagia and other hypothalamic abnormalities in this spontaneous obesity syndrome. The apparent absence of differences between the male corpulent and lean groups may relate to sexual dimorphism of the syndrome, which is more marked in the females.
Animals↗
Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression.
Expression of hormones in endocrine tumors and derived cell lines of transgenic mice carrying insulin-promoted oncogenes has been investigated by histochemical, immunohistochemical, ultrastructural, and radioimmunologic means. Tumors of the pancreas, small intestine, mesentery, and liver were examined. Insulin-immunoreactive cells were prevalent in pancreatic tumors, with a significant subpopulation of pancreatic polypeptide-immunoreactive elements. Conventional ultrastructural and immunogold analysis identified insulin-storing beta granules in pancreatic tumor cells. In contrast, the largest immunoreactive subpopulation of intestinal tumors expressed secretin (53% of total cells), followed by proglucagon-related peptides (15%), glucose-dependent insulinotropic polypeptide (7%), gastrin (7%), pancreatic polypeptide (2%), neurotensin (2%), and somatostatin (1%). No detectable immunoreactivity for either insulin or serotonin was observed. Electron microscopy and immunogold labeling showed that intestinal tumor cells contained secretin-storing S-type granules. Lymph node and liver tumors contained secretin-immunoreactive cells with ultrastructural features similar to those of intestinal tumors. In addition, high levels of circulating insulinlike and secretinlike immunoreactants were detectable. Analogous hormone profiles were identified in tumor cell lines and culture media. Large T-antigen immunoreactivity was detected in all the nuclei of neoplastic cells, as well as in insulin-immunoreactive elements of non-neoplastic islets and pancreatic ducts and in some secretin-immunoreactive cells of small intestinal mucosa. These data indicate that neuroendocrine tumors arise both in beta cell and S-cell subpopulations of transgenic mice.
Animals↗
Characterization of glucagon-like peptide-1-(7-36)amide in the hypothalamus.
The distribution of glucagon-like peptide-1-(7-36)amide like immunoreactivity (GLP-1-(7-36)NH2 IR) in rat brain was determined. Highest concentrations were found in the hypothalamus. A combination of gel chromatography and anion exchange chromatography showed that the majority of hypothalamic immunoreactivity exactly corresponded in position to synthetic GLP-1-(7-36)NH2. Chromatographic analyses of rat ileum demonstrated a similar pattern, whereas in rat pancreas mainly a large proglucagon fragment and GLP-1 were indicated. Determination of the subcellular distribution by differential centrifugation of hypothalamic tissue revealed that most of the GLP-1-(7-36)NH2 IR was present in the synaptosome fraction. GLP-1-(7-36)NH2 was released from hypothalamic tissue slices in a calcium-dependent fashion by potassium-induced depolarization. Thus GLP-1-(7-36)NH2 appears to fulfil two criteria for a neurotransmitter. No change was found in its hypothalamic content in streptozocin-induced diabetic rats compared to normal controls but a decrease was seen in hyperinsulinemic hyperglycemic KKAy mice compared to KK mice.
Animals↗